The ideal therapy for rate-control in patients in cardiac arrhythmia, e.g., AF, will be one that is safe, well tolerated, that can be quickly and easily delivered, has fast onset to effect, and exhibits a duration of effect for several hours after a single or repeated administration for in- and out-of-hospital use. This is a difficult goal to achieve, e.g., not met by any of the current therapies available to manage patients with atrial fibrillation.
Effective methods, formulations, and kits are needed to address a potential life-threatening condition associated with acute cardioversion of atrial fibrillation (AF) in particular with class 1c agents such as flecainide. During conversion of AF to normal sinus rhythm a transient rhythm called atrial flutter may occur. If atrioventricular (AV) nodal conduction (transmission) is not slowed, atrial flutter with 1:1 AV conduction may emerge, resulting in a very fast ventricular rate, akin to ventricular tachycardia. Atrial flutter with 1:1 conduction is associated with severe haemodynamic instability and potentially progression to ventricular fibrillation. This can become a life-threatening condition.
Beta blockers, also written as β-blockers, are a class of drugs that can be cardio-selective and can be used to modulate, e.g., to slow the ventricular heart rate in patients with AF—what is called the “rate control strategy” for the management of patients with AF. Beta blockers may selectively block β-adrenergic receptors, such as β1 adrenergic receptors (β1AR).
Currently, β1AR blockers are delivered intravenously and/or as oral tablets. Although IV or oral administration of β1AR blockers is used for rate control (e.g., slowing ventricular rate) in patients with atrial fibrillation, they have not been proven superior to placebo for acute conversion of nonpostoperative atrial fibrillation (McNamara et al. Ann. Intern. Med. 2003, 139:1018-1033). Currently β1AR blockers, either PO or IV, are not recommended in use for acute conversion of atrial fibrillation to normal sinus rhythm. For instance, soltalol, a noncardioselective β1AR (it can also block potassium channels) has been reported in several studies to have efficacy (when given in oral pills) for acute conversion of atrial fibrillation to normal sinus rhythm in the range of 8-49% (reviewed in Ferreira et al. Pharmacotherapy 1997; 17:1233-1237). Another commonly used β1AR blocker, metoprolol, when given intravenously (5 to 15 mg bolus doses) was reported to have a conversion rate of atrial arrhythmia of 13% only, although was effective in reducing the rate for at least 25% or reducing it to less than 100 bpm in 68% of the patients (Rehnqvist N., Ann. Clin. Res. 1981; 13 Suppl 30:68-72). In another study (Platia E V, et al. Am. J. Cardiol. 1989; 63:925-929), about 50% of esmolol-treated patients with new onset atrial fibrillation or flutter converted to sinus rhythm.
Drugs administered via the IV route are significantly diluted in the venous blood volume and lungs before reaching the cardiac circulation. For example, they may have a short half-life and may require continuous infusion for a long period of time, which can preclude unassisted safe use of this drug by patients at-home. Some β1AR blockers, when delivered orally, may be absorbed slowly and only reach mean peak plasma concentrations from 0.5 hours post dosing in some patients up to 2 hours post-dosing. This may be due to variability in first-pass metabolism; some patients are extensive metabolizers while others are poor metabolizers. This variability may complicate determining the appropriate dose for a given patient, thus requiring careful titration for each patient, as a dose that is too low may not be effective, and a dose that is too high may result in undesirable side effects.